Velocity-selective arterial spin labeling perfusion measurements in 2nd trimester human placenta with varying BMI.

INTRODUCTION: Proper placental development is crucial to fetal health but is challenging to functionally assess non-invasively and is thus poorly characterized in populations. Body mass index (BMI) has been linked with adverse outcomes, but the causative mechanism is uncertain. Velocity-selective arterial spin labeling (VS-ASL) MRI provides a method to non-invasively measure placental perfusion with robustness to confounding transit time delays. In this study, we report on the measurement of perfusion in the human placenta in early pregnancy using velocity-selective arterial spin labeling (VS-ASL) MRI, comparing non-obese and obese participants. METHODS: Participants (N = 97) undergoing routine prenatal care were recruited and imaged with structural and VS-ASL perfusion MRI at 15 and 21 weeks gestation. Resulting perfusion images were analyzed with respect to obesity based on BMI, gestational age, and the presence of adverse outcomes. RESULTS: At 15 weeks gestation BMI was not associated with placental perfusion or perfusion heterogeneity. However, at 21 weeks gestation BMI was associated with higher placental perfusion (p < 0.01) and a decrease in perfusion heterogeneity (p < 0.05). In alignment with past studies, perfusion values were also higher at 21 weeks compared to 15 weeks gestation. In a small cohort of participants with adverse outcomes, at 21 weeks lower perfusion was observed compared to participants with uncomplicated pregnancies. DISCUSSION: These results suggest low placental perfusion in the early second trimester may not be the culpable factor driving associations of obesity with adverse outcomes.

Assessment of feto-placental oxygenation and perfusion in a rat model of placental insufficiency using T2* mapping and 3D dynamic contrast-enhanced MRI.

INTRODUCTION: Placental insufficiency may lead to preeclampsia and fetal growth restriction. There is no cure for placental insufficiency, emphasizing the need for monitoring fetal and placenta health. Current monitoring methods are limited, underscoring the necessity for imaging techniques to evaluate fetal-placental perfusion and oxygenation. This study aims to use MRI to evaluate placental oxygenation and perfusion in the reduced uterine perfusion pressure (RUPP) model of placental insufficiency. METHODS: Pregnant rats were randomized to RUPP (n = 11) or sham surgery (n = 8) on gestational day 14. On gestational day 19, rats imaged using a 7T MRI scanner to assess oxygenation and perfusion using T2* mapping and 3D-DCE MRI sequences, respectively. The effect of the RUPP on the feto-placental units were analyzed from the MRI images. RESULTS: RUPP surgery led to reduced oxygenation in the labyrinth (24.7 ± 1.8 ms vs. 28.0 ± 2.1 ms, P = 0.002) and junctional zone (7.0 ± 0.9 ms vs. 8.1 ± 1.1 ms, P = 0.04) of the placenta, as indicated by decreased T2* values. However, here were no significant differences in fetal organ oxygenation or placental perfusion between RUPP and sham animals. DISCUSSION: The reduced placental oxygenation without a corresponding decrease in perfusion suggests an adaptive response to placental ischemia. While acute reduction in placental perfusion may cause placental hypoxia, persistence of this condition could indicate chronic placental insufficiency after ischemic reperfusion injury. Thus, placental oxygenation may be a more reliable biomarker for assessing fetal condition than perfusion in hypertensive disorders of pregnancies including preeclampsia and FGR.

Pentaerythrityl tetranitrate improves the outcome of children born to mothers with compromised uterine perfusion-12-months follow-up and safety data of the double-blind randomized PETN trial.

BACKGROUND: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age. OBJECTIVE: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial. STUDY DESIGN: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion. RESULTS: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups. CONCLUSION: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

Placental size at gestational week 27 and 37: The associations with pulsatility index in the uterine and the fetal-placental arteries.

INTRODUCTION: Fetal growth restriction is known to be related to decreased fetal and placental blood flow. It is not known, however, whether placental size is related to fetal and placental blood flow. We studied the correlations of intrauterine placental volume and placental-fetal-ratio with pulsatility index (PI) in the uterine arteries, fetal middle cerebral artery, and umbilical artery. METHODS: We followed a convenience sample of 104 singleton pregnancies, and we measured placental and fetal volumes using magnetic resonance imaging (MRI) at gestational week 27 and 37 (n = 89). Pulsatility index (PI) was measured using Doppler ultrasound. We calculated cerebroplacental ratio as fetal middle cerebral artery PI/umbilical artery PI and placental-fetal-ratio as placental volume (cm3)/fetal volume (cm3). RESULTS: At gestational week 27, placental volume was negatively correlated with uterine artery PI (r = -0.237, p = 0.015, Pearson's correlation coefficient), and positively correlated with fetal middle cerebral artery PI (r = 0.247, p = 0.012) and cerebroplacental ratio (r = 0.208, p = 0.035). Corresponding correlations for placental-fetal-ratio were -0.273 (p = 0.005), 0.233 (p = 0.018) and 0.183 (p = 0.064). Umbilical artery PI was not correlated with placental volume. At gestational week 37, we found weaker and no significant correlations between placental volume and the pulsatility indices. CONCLUSIONS: Our results suggest that placental size is correlated with placental and fetal blood flow at gestational week 27.

Fetoplacental vascular effects of maternal adrenergic antihypertensive and cardioprotective medications in pregnancy.

Maternal cardiovascular diseases, including hypertension and cardiac conditions, are associated with poor fetal outcomes. A range of adrenergic antihypertensive and cardioprotective medications are often prescribed to pregnant women to reduce major maternal complications during pregnancy. Although these treatments are not considered teratogenic, they may have detrimental effects on fetal growth and development, as they cross the fetoplacental barrier, and may contribute to placental vascular dysregulation. Medication risk assessment sheets do not include specific advice to clinicians and women regarding the safety of these therapies for use in pregnancy and the potential off-target effects of adrenergic medications on fetal growth have not been rigorously conducted. Little is known of their effects on the fetoplacental vasculature. There is also a dearth of knowledge on adrenergic receptor activation and signalling within the endothelium and vascular smooth muscle cells of the human placenta, a vital organ in the maintenance of adequate blood flow to satisfy fetal growth and development. The fetoplacental circulation, absent of sympathetic innervation, and unique in its reliance on endocrine, paracrine and autocrine influence in the regulation of vascular tone, appears vulnerable to dysregulation by adrenergic antihypertensive and cardioprotective medications compared with the adult peripheral circulation. This semi-systematic review focuses on fetoplacental vascular expression of adrenergic receptors, associated cell signalling mechanisms and predictive consequences of receptor activation/deactivation by antihypertensive and cardioprotective medications.

A review of feto-placental vasculature flow modelling.

The placenta provides the vital nutrients and removal of waste products required for fetal growth and development. Understanding and quantifying the differences in structure and function between a normally functioning placenta compared to an abnormal placenta is vital to provide insights into the aetiology and treatment options for fetal growth restriction and other placental disorders. Computational modelling of blood flow in the placenta allows a new understanding of the placental circulation to be obtained. This structured review discusses multiple recent methods for placental vascular model development including analysis of the appearance of the placental vasculature and how placental haemodynamics may be simulated at multiple length scales.

Blood Flow and Respiratory Gas Exchange in the Human Placenta at Term: A Data Update.

Reliable measurements using modern techniques and consensus in experimental design have enabled the assessment of novel data sets for normal maternal and foetal respiratory physiology at term. These data sets include (a) principal factors affecting placental gas transfer, e.g., maternal blood flow through the intervillous space (IVS) (500 mL/min) and foeto-placental blood flow (480 mL/min), and (b) O2, CO2 and pH levels in the materno-placental and foeto-placental circulation. According to these data, the foetus is adapted to hypoxaemic hypoxia. Despite flat oxygen partial pressure (pO2) gradients between the blood of the IVS and the umbilical arteries of the foetus, adequate O2 delivery to the foetus is maintained by the higher O2 affinity of the foetal blood, high foetal haemoglobin (HbF) concentrations, the Bohr effect, the double-Bohr effect, and high foeto-placental (=umbilical) blood flow. Again, despite flat gradients, adequate CO2 removal from the foetus is maintained by a high diffusion capacity, high foeto-placental blood flow, the Haldane effect, and the double-Haldane effect. Placental respiratory gas exchange is perfusion-limited, rather than diffusion-limited, i.e., O2 uptake depends on O2 delivery.

Impact of reduced uterine perfusion pressure model of preeclampsia on metabolism of placenta, maternal and fetal hearts.

Preeclampsia is a cardiovascular pregnancy complication characterised by new onset hypertension and organ damage or intrauterine growth restriction. It is one of the leading causes of maternal and fetal mortality in pregnancy globally. Short of pre-term delivery of the fetus and placenta, treatment options are limited. Consequently, preeclampsia leads to increased cardiovascular disease risk in both mothers and offspring later in life. Here we aim to examine the impact of the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia on the maternal cardiovascular system, placental and fetal heart metabolism. The surgical RUPP model was induced in pregnant rats by applying silver clips around the aorta and uterine arteries on gestational day 14, resulting in ~ 40% uterine blood flow reduction. The experiment was terminated on gestational day 19 and metabolomic profile of placentae, maternal and fetal hearts analysed using high-resolution 1H NMR spectroscopy. Impairment of uterine perfusion in RUPP rats caused placental and cardiac hypoxia and a series of metabolic adaptations: altered energetics, carbohydrate, lipid and amino acid metabolism of placentae and maternal hearts. Comparatively, the fetal metabolic phenotype was mildly affected. Nevertheless, long-term effects of these changes in both mothers and the offspring should be investigated further in the future.

The placenta and preeclampsia: villain or victim?

Preeclampsia is a disease whose characterization has not changed in the 150 years since the cluster of signs associated with the disorder were first described. Although our understanding of the pathophysiology of preeclampsia has advanced considerably since then, there is still little consensus regarding the true etiology of preeclampsia. As a consequence, preeclampsia has earned the moniker "disease of theories," predominantly because the underlying biological mechanisms linking clinical epidemiologic findings to observed organ dysfunction in preeclampsia are far from clear. Despite the lack of cohesive evidence, expert consensus favors the hypothesis that preeclampsia is a primary placental disorder. However, there is now emerging evidence that suboptimal maternal cardiovascular performance resulting in uteroplacental hypoperfusion is more likely to be the cause of secondary placental dysfunction in preeclampsia. Preeclampsia and cardiovascular disease share the same risk factors, preexisting cardiovascular disease is the strongest risk factor (chronic hypertension, congenital heart disease) for developing preeclampsia, and there are now abundant data from maternal echocardiography and angiogenic marker studies that cardiovascular dysfunction precedes the development of preeclampsia by several weeks or months. Importantly, cardiovascular signs and symptoms (hypertension, cerebral edema, cardiac dysfunction) predominate in preeclampsia at clinical presentation and persist into the postnatal period with a 30% risk of chronic hypertension in the decade after birth. Placental malperfusion caused by suboptimal maternal cardiovascular performance may lead to preeclampsia, thereby explaining the preponderance of cardiovascular drugs (aspirin, calcium, statins, metformin, and antihypertensives) in preeclampsia prevention strategies. Despite the seriousness of the maternal and fetal consequences, we are still developing sensitive screening, reliable diagnostic, effective therapeutic, or improvement strategies for postpartum maternal cardiovascular legacy in preeclampsia. The latter will only become clear with an acceptance and understanding of the cardiovascular etiology of preeclampsia.

S100B in maternal circulation of pregnancies complicated by FGR and brain sparing.

OBJECTIVE: To determine whether the presence of brain sparing in fetal growth restricted (FGR) fetuses involves elevation of the cerebral injury biomarker S100B in maternal circulation. METHODS: We included 63 women with suspected small for gestational age (SGA) fetuses between 24 and 35 +6/7 weeks of gestation. Maternal plasma angiogenic factors measurements and sonographic evaluation were performed at recruitment. Next, we subdivided our SGA cohort into three groups: SGA fetuses, FGR fetuses without brain-sparing, and FGR fetuses with brain-sparing (FGR-BS). Serum S100B concentration was calculated as S100B µg/L, S100B MoM, and the ratio S100B/ estimated fetal weight (EFW). We also report one case of S100B concentration surge in maternal serum following the diagnosis of fetal intraventricular hemorrhage (IVH). RESULTS: The FGR-BS group had higher maternal S100B µg/L (p < 0.01, p < 0.05, respectively), S100B MoM (p < 0.001, p < 0.001, respectively), and S100B/EFW (p < 0.001, p < 0.01, respectively), compared to the SGA and FGR groups. In the case report, maternal serum S100B concentrations were 0.0346 µg/L before, and 0.0874 µg/L after IVH occurrence. CONCLUSIONS: S100B concentration in maternal serum increased in pregnancies complicated by FGR and brain sparing. These results may substantiate in-utero cerebral injury and may explain the adverse neurocognitive outcomes reported for this group.

Association of VEGF and p53 Polymorphisms and Spiral Artery Remodeling in Recurrent Pregnancy Loss: A Systematic Review and Meta-Analysis.

Many studies have reported the association of VEGF-1154G/A, VEGF 936C/T, and p53 Arg72Pro polymorphisms with recurrent pregnancy loss (RPL), but the outcomes are inconsistent. We have used a meta-analysis to associate these polymorphisms with RPL, having the spiral artery remodeling as a major risk factor. The studies were identified from three different reputed databases, namely ScienceDirect, PubMed/Medline, and Scopus. The eligible studies of VEGF-1154G/A, VEGF 936C/T, and p53Arg72Pro polymorphisms associated with the RPL were selected for the analysis. They were segregated into three different ethnic groups as Asians, Caucasians, and mixed population. For the analysis, the overall prevalence, odds ratio, risk ratio, relative risk ratio, and p-values were calculated. A total of 3,241 RPL cases and 3,205 healthy controls from 21 different case-control studies were analyzed. RPL was highly prevalent in the mixed population with VEGF-1154G/A and p53 Arg72Pro polymorphisms (70.04 and 66.46%, respectively) and in the Asian population with VEGF 936C/T polymorphism (53.58%). The homozygous recessive genotypes of VEGF and p53 exhibited significant association between the respective polymorphisms and RPL along with the increased risk of outcome. The current analysis conclusively reports the geographic distribution of the different genetic polymorphisms which shows high association with the progression of RPL. Understanding the spectrum of polymorphisms on different populations with the spiral artery remodeling as a risk factor encloses the importance of the vasculature during the pregnancy.

Periconceptional maternal and paternal homocysteine levels and early utero-placental (vascular) growth trajectories: The Rotterdam periconception cohort.

INTRODUCTION: Maternal elevated plasma total homocysteine (tHcy) is involved in the origin of several placenta-related pregnancy complications. The first trimester is the most sensitive period for placentation influenced by maternal and paternal health. The aim is to study associations between periconceptional parental tHcy levels and utero-placental growth trajectories in the first trimester of pregnancy. METHODS: Pregnant women and their partners were enrolled before 10 weeks of gestation in the Virtual Placenta study as subcohort of the Rotterdam periconception cohort (Predict study). A total of 190 women with a singleton pregnancy, of which 109 conceived naturally and 81 after IVF/ICSI treatment, were included. We measured serial utero-placental vascular volumes (uPVV) and placental volumes (PV) at 7, 9 and 11 weeks of gestation. First-trimester trajectories of PV were also measured in 662 pregnancies from the total Predict study. RESULTS: Comparing all participants of the virtual placenta study, no association between maternal tHcy and uPVV was observed. However, in IVF/ICSI pregnancies sub-analyses showed significantly negative associations between maternal tHcy in the 3rd and 4th quartile and uPVV trajectories (beta: -0.38 (95%CI -0.74 to -0.02) and beta: -0.42 (95% CI -0.78 to -0.05), respectively) with the 1st quartile as reference. Analysis in the total Predict cohort showed similar negative associations for the total study population. DISCUSSION: Periconceptional high maternal tHcy levels are associated with smaller placental growth trajectories depicted as PV and uPVV in the first trimester of pregnancy. The stronger negative associations with uPVV in IVF/ICSI pregnancies underline the need for further investigation.

Uteroplacental Circulation in Normal Pregnancy and Preeclampsia: Functional Adaptation and Maladaptation.

Uteroplacental blood flow increases as pregnancy advances. Adequate supply of nutrients and oxygen carried by uteroplacental blood flow is essential for the well-being of the mother and growth/development of the fetus. The uteroplacental hemodynamic change is accomplished primarily through uterine vascular adaptation, involving hormonal regulation of myogenic tone, vasoreactivity, release of vasoactive factors and others, in addition to the remodeling of spiral arteries. In preeclampsia, hormonal and angiogenic imbalance, proinflammatory cytokines and autoantibodies cause dysfunction of both endothelium and vascular smooth muscle cells of the uteroplacental vasculature. Consequently, the vascular dysfunction leads to increased vascular resistance and reduced blood flow in the uteroplacental circulation. In this article, the (mal)adaptation of uteroplacental vascular function in normal pregnancy and preeclampsia and underlying mechanisms are reviewed.

Ligadura del cordón umbilical en recién nacidos prematuros / Umbilical cord clamping in preterm infants

La prematiridad fue aumentando la supervivencia desde hace varios años, y eso produce, sobre todo, una preocupación en los prematuros nacidos antes de las 28 semanas de gestación. El tiempo del clampeo del cordón umbilical puede generar diversos trastornos, principalmente, cuando se realiza temprano (10-15 segundos). Ya desde hace 20 años, a través de varias investigaciones, se pudieron demostrar los notorios beneficios del clampeo demorado del cordón (de 2 a 3 minutos). Esta práctica fue instalada en la asistencia obstétrica y neonatal por las recomendaciones de sociedades científicas y de las revisiones sistemáticas, que señalaron las sólidas evidencias que apoyaban esta conducta para prematuros. En esta revisión, se describen los artículos más relevantes en los últimos años, que sustentan notoriamente la aplicación del clampeo demorado del cordón versus el clampeo temprano. Asimismo, esta práctica genera una disminución de los trastornos graves en prematuros.

For several years now, the survival of preterm infants has been increasing, which has shifted our concern to preterm infants born before 28 weeks of gestation in particular. The timing of umbilical cord clamping may lead to several disorders, especially when done early (10-15 seconds). In the last two decades, several investigations have shown the considerable benefits of delayed cord clamping (2-3 minutes). Delayed cord clamping has been practiced in obstetrics and neonatal care based on the recommendations made by scientific societies and in systematic reviews, which have provided solid evidence to support this practice in preterm infants. This review describes the most relevant articles from the last years, which strongly support the use of delayed cord clamping versus early cord clamping. In addition, this practice reduces the rate of severe disorders in preterm infants.

Trophoblast derived extracellular vesicles specifically alter the transcriptome of endometrial cells and may constitute a critical component of embryo-maternal communication.

BACKGROUND: The period of time when the embryo and the endometrium undergo significant morphological alterations to facilitate a successful implantation-known as "window of implantation"-is a critical moment in human reproduction. Embryo and the endometrium communicate extensively during this period, and lipid bilayer bound nanoscale extracellular vesicles (EVs) are purported to be integral to this communication. METHODS: To investigate the nature of the EV-mediated embryo-maternal communication, we have supplemented trophoblast analogue spheroid (JAr) derived EVs to an endometrial analogue (RL 95-2) cell layer and characterized the transcriptomic alterations using RNA sequencing. EVs derived from non-trophoblast cells (HEK293) were used as a negative control. The cargo of the EVs were also investigated through mRNA and miRNA sequencing. RESULTS: Trophoblast spheroid derived EVs induced drastic transcriptomic alterations in the endometrial cells while the non-trophoblast cell derived EVs failed to induce such changes demonstrating functional specificity in terms of EV origin. Through gene set enrichment analysis (GSEA), we found that the response in endometrial cells was focused on extracellular matrix remodelling and G protein-coupled receptors' signalling, both of which are of known functional relevance to endometrial receptivity. Approximately 9% of genes downregulated in endometrial cells were high-confidence predicted targets of miRNAs detected exclusively in trophoblast analogue-derived EVs, suggesting that only a small proportion of reduced expression in endometrial cells can be attributed directly to gene silencing by miRNAs carried as cargo in the EVs. CONCLUSION: Our study reveals that trophoblast derived EVs have the ability to modify the endometrial gene expression, potentially with functional importance for embryo-maternal communication during implantation, although the exact underlying signalling mechanisms remain to be elucidated.

MIUH Inhibits the Hippocampal Neuron Growth in Fetal Rat by Affecting the PTEN Pathway.

Mild intrauterine hypoperfusion (MIUH) can induce placental dysfunction and lead to long-term changes during the process of brain development. A better understanding of the mechanism of MIUH will help in the development of new neuroprotective strategies for the placental chamber. To better understand the mechanism of the effect of MIUH on the neural development of offspring, we constructed a model of MIUH in pregnant rats. The proliferation, apoptosis, and autophagy of hippocampal neurons in fetal rats were studied via flow cytometry, immunofluorescence staining, JC-1 staining, western blotting, and real-time polymerase chain reaction at different time points (6, 24, 48, and 72 h). The results showed that MIUH significantly inhibited the proliferation of hippocampal neurons and promoted their apoptosis and autophagy. Simultaneously, MIUH could promote PTEN expression and affect the PTEN signaling pathway. bpV, an inhibitor of PTEN, could restore the inhibition of hippocampal nerve cell growth caused by MIUH. MIUH may inhibit neuronal proliferation and promote neuronal apoptosis and autophagy by regulating the PTEN signaling pathway.

Enhanced Nitrite-Mediated Relaxation of Placental Blood Vessels Exposed to Hypoxia Is Preserved in Pregnancies Complicated by Fetal Growth Restriction.

Nitric oxide (NO) is essential in the control of fetoplacental vascular tone, maintaining a high flow-low resistance circulation that favors oxygen and nutrient delivery to the fetus. Reduced fetoplacental blood flow is associated with pregnancy complications and is one of the major causes of fetal growth restriction (FGR). The reduction of dietary nitrate to nitrite and subsequently NO may provide an alternative source of NO in vivo. We have previously shown that nitrite induces vasorelaxation in placental blood vessels from normal pregnancies, and that this effect is enhanced under conditions of hypoxia. Herein, we aimed to determine whether nitrite could also act as a vasodilator in FGR. Using wire myography, vasorelaxant effects of nitrite were assessed on pre-constricted chorionic plate arteries (CPAs) and veins (CPVs) from normal and FGR pregnancies under normoxic and hypoxic conditions. Responses to the NO donor, sodium nitroprusside (SNP), were assessed in parallel. Nitrate and nitrite concentrations were measured in fetal plasma. Hypoxia significantly enhanced vasorelaxation to nitrite in FGR CPAs (p < 0.001), and in both normal (p < 0.001) and FGR (p < 0.01) CPVs. Vasorelaxation to SNP was also potentiated by hypoxia in both normal (p < 0.0001) and FGR (p < 0.01) CPVs. However, compared to vessels from normal pregnancies, CPVs from FGR pregnancies showed significantly lower reactivity to SNP (p < 0.01). Fetal plasma concentrations of nitrate and nitrite were not different between normal and FGR pregnancies. Together, these data show that nitrite-mediated vasorelaxation is preserved in FGR, suggesting that interventions targeting this pathway have the potential to improve fetoplacental blood flow in FGR pregnancies.

Rhythm of Fetoplacental 11ß-Hydroxysteroid Dehydrogenase Type 2 - Fetal Protection From Morning Maternal Glucocorticoids.

CONTEXT: Excess glucocorticoids impact fetal health. Maternal glucocorticoids peak in early morning. Fetoplacental 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) inactivates cortisol to cortisone, protecting the fetus from high glucocorticoids. However, time-specific alterations of human fetoplacental 11ß-HSD2 have not been studied. OBJECTIVE: We hypothesized that fetoplacental 11ß-HSD2 activity shows time-specific alteration and acute affective or anxiety disorders impact fetoplacental 11ß-HSD2 activity. METHODS: In this observational study we investigated 78 pregnant European women undergoing amniocentesis (15.9 ± 0.9 weeks of gestation). Amniotic fluid was collected (8:00 to 16:30 hours) for analysis of fetoplacental 11ß-HSD2 activity, using cortisol (F):cortisone (E) ratio in amniotic fluid, E/(E + F). Fetoplacental 11ß-HSD2 rhythm and association with "acute affective or anxiety disorder" (patients with at least one of: a major depressive episode, specific phobia, panic disorder, generalized anxiety disorder, mixed anxiety and depressive disorder) and "acute anxiety disorder" (one of: panic disorder, generalized anxiety disorder, mixed anxiety, depressive disorder), assessed using Mini International Neuropsychiatric Interview, were investigated. RESULTS: Activity of 11ß-HSD2 correlated with time of amniocentesis, peaking in the morning (r = -0.398; P < 0.001) and increased with acute affective or anxiety disorder (mean [M] = 0.70 vs M = 0.74; P = 0.037) and acute anxiety disorder (M = 0.70 vs M = 0.75; P = 0.016). These associations remained significant when controlling for confounders. 11ß-HSD2 activity correlated negatively with pre-pregnancy body mass index (r = -0.225; P = 0.047). CONCLUSION: Our study indicates a time-specific alteration of fetoplacental 11ß-HSD2 activity with peaking levels in the morning, demonstrating a mechanism of fetal protection from the morning maternal glucocorticoid surge.

Understanding the uterine artery Doppler waveform and its relationship to spiral artery remodelling.

Analysis of the uterine artery (UtA) Doppler waveform is frequently used in high-risk pregnancies to assess the likelihood of adverse pregnancy outcomes, including preeclampsia and fetal growth restriction. Whilst abnormal UtA waveforms at 18-20 weeks are associated with adverse outcomes, the underlying cause of these waveform changes remains unknown. Current evidence suggests the long-held dogma that the UtA waveform is merely a reflection of trophoblast-induced spiral artery remodelling is incorrect. Hence, the origins of the waveform changes must be reassessed. Recent data from human and animal models suggests that the arcuate arteries, placental bed arterio-venous anastomoses and, most notably, the radial arteries may be more important in determining the UtA waveform profile than previously appreciated. Furthermore, there is increasing evidence implicating the maternal cardiovascular system in the pathophysiology of the complications predicted by the waveform changes, particularly preeclampsia, and therefore its underlying association with the UtA waveform warrants further investigation.

Role of heme oxygenase-1 in human placenta on iron supply to fetus.

INTRODUCTION: To date, details on how iron is supplied from the mother to the fetus through the placenta have remained unclear. Recently, increasing evidence has shown that heme oxygenase (HO)-1, which is an inducible isoform of the rate-limiting enzyme in the heme degradation pathway, may be involved in the effective reutilization of iron. In this study, we examined the distribution and gene expression of HO-1 in the villous tissue of human placenta at various periods of pregnancy. METHODS: Using the placenta of 38 samples for which consent was obtained, chronological changes in the localization of HO-1 protein were examined by histological examination. RT-PCR was also performed to examine the expression of HO-1, transferrin receptor-1, and ferroportin 1. Ferric iron in the tissues was analyzed by Prussian blue staining. RESULTS: Immunohistochemical studies showed that HO-1 protein was exclusively expressed in trophoblastic cells throughout gestation. In the miscarriage placenta in the first trimester, ho-1 mRNA levels were significantly higher than normal. Placenta with fetal death (miscarriage) in the first and second trimester indicate significantly higher ratio of ho-1 gene for iron production to the fpn-1 gene for iron excretion than normal. These suggest that the role of HO-1 with various physiological functions is changing throughout pregnancy. DISCUSSION: These findings suggest that HO-1 in placenta plays an important role in iron supplying system in the second trimester to support fetal development.